Comparison of tumor targeting in nude mice by murine monoclonal antibodies directed against different human colorectal cancer antigens.
Tumor targeting of five radioiodinated murine monoclonal antibodies (MAbs) directed against human colorectal cancer were studied in nude mice bearing the GW-39 human colonic tumor xenograft. All of the MAbs are of the IgG1 isotype. Two of the MAbs (NP-4 and MN-14) are directed against a Class III carcinoembryonic antigen-specific epitope, but they differ 10-fold in their affinity. The other three MAbs recognize mucins found in colonic cancer. Mu-9 recognizes a peptide determinant similar to that described previously for a polyclonal goat anti-colon-specific antigen p. G9 identifies an organ-specific, tumor-associated carbohydrate epitope. The tumor targeting of these MAbs was compared to that of B72.3, another anti-mucin MAb. The tumor uptake of all the MAbs were similar on days 1, 3, and 7, with an average maximum accretion of between 30 and 40%/g tumor occurring by day 3. This tumor uptake was maintained for 14 days with the anti-mucin MAbs, whereas the percentage of injected dose/g in the tumor for 2 anti-carcinoembryonic antigen MAbs decreased 2-fold by day 14. Although no statistical difference could be found between the percentage of injected dose/g in the tumor for NP-4 and MN-14 (carcinoembryonic antigen MAbs), in a paired-labeled study using 131I-MN-14 and 125I-NP-4, MN-14 uptake in the tumor was consistently 1.3 times higher than that of NP-4 on all days tested. F(ab')2 fragments showed lower tumor uptake (maximum uptake for NP-4 and Mu-9 was 11% on day 1), but the faster clearance resulted in a 4- to 40-fold increase in tumor/blood ratios on day 3 in comparison to the whole IgGs. Fab' fragments had the lowest tumor uptake of the 3 forms of immunoglobulin, with a maximum of only 5%/g 6 h after injection. However, tumor/blood ratios on day 1 for the Fab' fragments were improved 3-fold over that of F(ab')2. All of these MAbs, except Mu-9, identify epitopes that can be detected in plasma, but none of the MAbs complexed appreciably when mixed in vitro with plasma containing antigen at antigen/MAb ratios anticipated to be encountered most frequently in imaging or therapy applications in humans. However, complexation of the MAbs will occur if antigen in the plasma is markedly elevated. These studies suggest that if used clinically, tumor targeting of colorectal cancer with any of these MAb IgG may be similar if these antigens are present at relatively similar concentrations in tumor.(ABSTRACT TRUNCATED AT 400 WORDS)
Sharkey
R M
RM
Center for Molecular Medicine and Immunology, University of Medicine and Dentistry of New Jersey, Newark.
Gold
D V
DV
Aninipot
R
R
Vagg
R
R
Ballance
C
C
Newman
E S
ES
Ostella
F
F
Hansen
H J
HJ
Goldenberg
D M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000032:analysis; D000951:Antigens, Neoplasm / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D051379:Mice; D008819:Mice, Nude; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D007457:Iodine Radioisotopes